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J Physiol. 2012 Sep 1;590(17):4201-8. doi: 10.1113/jphysiol.2012.233353. Epub 2012 May 28.

STIM/Orai signalling complexes in vascular smooth muscle.

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  • 1The Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA.


Stromal interaction molecules (STIM1 and STIM2) are single pass transmembrane proteins located mainly in the endoplasmic reticulum (ER). STIM proteins contain an EF-hand in their N-termini that faces the lumen side of the ER allowing them to act as ER calcium (Ca(2+)) sensors. STIM1 has been recognized as central to the activation of the highly Ca(2+) selective store-operated Ca(2+) (SOC) entry current mediated by the Ca(2+) release-activated Ca(2+) (CRAC) channel; CRAC channels are formed by tetramers of the plasma membrane (PM) protein Orai1. Physiologically, the production of inositol 1,4,5-trisphosphate (IP(3)) upon stimulation of phospholipase C-coupled receptors and the subsequent emptying of IP(3)-sensitive ER Ca(2+) stores are sensed by STIM1 molecules which aggregate and move closer to the PM to interact physically with Orai1 channels and activate Ca(2+) entry. Orai1 has two homologous proteins encoded by separate genes, Orai2 and Orai3. Other modes of receptor-regulated Ca(2+) entry into cells are store-independent; for example, arachidonic acid activates a highly Ca(2+) selective store-independent channel formed by heteropentamers of Orai1 and Orai3 and regulated by the PM pool of STIM1. Here, I will discuss results pertaining to the roles of STIM and Orai proteins in smooth muscle Ca(2+) entry pathways and their role in vascular remodelling.

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